A Narrative Review of Poland's Syndrome

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Review Article

A narrative review of Poland’s syndrome: theories of its genesis, evolution and its diagnosis and treatment

Eman Awadh Abduladheem Hashim1,2^, Bin Huey Quek1,3,4^, Suresh Chandran1,3,4,5^

1Department of Neonatology, KK Women’s and Children’s Hospital, Singapore, Singapore; 2Department of Neonatology, Salmanya Medical Complex, Manama, Kingdom of Bahrain; 3Department of Neonatology, Duke-NUS Medical School, Singapore, Singapore; 4Department of Neonatology, NUS Yong Loo Lin School of Medicine, Singapore, Singapore; 5Department of Neonatology, NTU Lee Kong Chian School of Medicine, Singapore, Singapore Contributions: (I) Conception and design: EAA Hashim, S Chandran; (II) Administrative support: S Chandran, BH Quek; (III) Provision of study materials: EAA Hashim, S Chandran; (IV) Collection and assembly: All authors; (V) Data analysis and interpretation: BH Quek, S Chandran; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Correspondence to: A/Prof. Suresh Chandran. Senior Consultant, Department of Neonatology, KK Women’s and Children’s Hospital, Singapore 229899, Singapore. Email: [email protected].

Abstract: Poland’s syndrome (PS) is a rare musculoskeletal congenital anomaly with a wide spectrum of presentations. It is typically characterized by hypoplasia or aplasia of pectoral muscles, mammary hypoplasia and variably associated ipsilateral limb anomalies. Limb defects can vary in severity, ranging from syndactyly to phocomelia. Most cases are sporadic but familial cases with intrafamilial variability have been reported. Several theories have been proposed regarding the genesis of PS. Vascular disruption theory, “the subclavian artery supply disruption sequence” (SASDS) remains the most accepted pathogenic mechanism. Clinical presentations can vary in severity from syndactyly to phocomelia in the limbs and in the thorax, rib defects to severe chest wall anomalies with impaired lung function. Most patients have subtle presentation at birth and milder forms in childhood. Functional limitations due to PS are usually minimal. Surgical treatment aims to improve pulmonary functions arising from severe thoracic deformities but is more often done to enhance the cosmesis. The use of adipose-derived mesenchymal stem cells and fat transfer have shown promising results in recent times for correction of chest defects and breast augmentation. Gaining deeper insights into the etiopathogenesis and clinical presentation of PS will improve the clinical recognition and management of this rare condition. In this review article, we aim to outline the details of this syndrome including its etiopathogenesis, evolution, spectrum of clinical manifestations, other systemic associations, diagnostic modalities, and recent advances in treatment.

Keywords: Poland’s syndrome (PS); pectoralis muscle hypoplasia; vascular disruption sequence; breast hypoplasia; brachysyndactyly

Submitted Oct 05, 2020. Accepted for publication Jan 29, 2021. doi: 10.21037/tp-20-320 View this article at: http://dx.doi.org/10.21037/tp-20-320

Introduction of pectoralis minor muscle in addition to brachysyndactyly of the ipsilateral hand, underdeveloped serratus anterior In his autopsy report, Alfred Poland expounded the muscle and remarkably small thoracic vessels (1,2). “deficiency of pectoral muscles” as deficient sternal and Absence of the sternal head of pectoralis major muscle is costal portions of the pectoralis major muscle and absence an essential feature of Poland’s syndrome (PS) and most

^ORCID: Eman Awadh Abduladheem Hashim, 0000-0002-4402-5301; Bin Huey Quek, 0000-0001-8891-5464; Suresh Chandran, 0000- 0001-5961-7441.

© Translational Pediatrics. All rights reserved. Transl Pediatr 2021;10(4):1008-1019 | http://dx.doi.org/10.21037/tp-20-320 Translational Pediatrics, Vol 10, No 4 April 2021 1009 often it manifests also as ipsilateral thoracic cage and the forearm and hand (10). Later it was Thompson who upper limb anomalies. Other recognized features of PS identified the principal features of PS and summarized the include aplasia/hypoplasia of the pectoralis minor muscle complete spectrum of congenital anomalies (11). Baudinne and breast/nipple, rib anomalies, dextrocardia, urogenital et al. referred to Poland’s syndactyly as PS (12). Controversy anomalies and axillary alopecia (3). Clinical features of PS remains around the eponymous origin of PS (6,13). are phenotypically variable and manifestations are often subtle in infancy and early childhood delaying the diagnosis Etiopathogenesis and plan for intervention. This review aims to improve the understanding of PS among medical fraternity about its Researchers have been debating on the etiology of PS for genesis, spectrum of clinical manifestations, diagnostic tools more than three decades. Several theories and etiological and recent advances in therapeutic modalities. factors have been suggested. Being a congenital disorder, We extensively relied upon Medline and EMBASE birth defects occur due to an error in morphogenesis database search to obtain relevant papers and their cited resulting in malformations, deformations, or disruptions. references, in addition to our personal clinical experience Embryonic or fetal vascular disruption can cause disruption and publications of PS with lung herniation and eventration sequences and the incidence was reported to be 0.1/1,000 of diaphragm to prepare this review (4). We present the infants born with more than one structural anomaly (14). following article in accordance with the Narrative Review Vascular disruption theory remains the most accepted reporting checklist (available at http://dx.doi.org/10.21037/ pathogenic mechanism. The likely pathogenesis of PS tp-20-320). may be due to disruption of development of the proximal subclavian artery and its branches that supply the pectoral muscles around 6th week of gestation. This further leads Historical perspective to deficient blood flow to the distal limb and pectoral PS was first described by Alfred Poland nearly 180 years region causing regional loss of tissue. Bavinck & Weaver ago based on an autopsy at Guy’s Hospital of a 27-year- presented a pathogenic hypothesis and introduced the term old ex-convict named George Elt (1). Several depictions called “the subclavian artery supply disruption sequence” about this musculoskeletal anomaly similar to that of Alfred (SASDS) to describe the disruption of embryonic vessels, Poland’s autopsy record predated the official publication in suggesting a common pathogenesis in PS, Klippel-Feil and Guy’s Hospital Reports [1841]. On 11th December 1803, Moebius syndromes (15). Predictable patterns of defects as “Citizen Marandel” presented in the second session of the a consequence of SASDS were described as follows: Société Anatomique de Paris a description of a woman with  Absence of pectoralis major and ipsilateral breast congenital mammary absence and muscular atrophy (sterno- hypoplasia due to interruption of internal thoracic humeral and costo-coracoid) on the right side, similar to the artery flow. observations of Poland (5,6). Absence of pectoral muscles  Terminal transverse limb defect following a alone was described earlier (7). In 1839, Froriep was the disruption of subclavian artery distal to the origin first to describe the paired absence of pectoral muscles and of internal thoracic artery. webbed digits (8). Even though Alfred Poland described the  PS resulting from a disruption of subclavian artery characteristics of this syndrome, it was Patrick Clarkson, distal to the origin of the vertebral artery but a plastic and hand surgeon working at Guy’s Hospital, proximal to the origin of internal thoracic artery. London, who coined the term “Poland’s syndactyly” (2).  Klippel-Feil syndrome caused by an interruption Clarkson noted a clear description of this paired deformity of blood flow through entire length or segments of in a review by Brown & McDowell who referred to Poland’s vertebral arteries. original report (9). Clarkson also retrieved the dissected  Moebius syndrome resulting from early regression specimen of the hand by Poland from the Curator of the of the primitive trigeminal arteries and/or delayed Gordon Museum and confirmed the syndactyly between formation of or obstruction in basilar and/or the index and middle finger. Later, McDowell criticized the vertebral arteries. eponym and argued that “Poland hadn’t the foggiest notion Data of decreased size and low velocity flow of subclavian that the two deformities constituted a syndrome” because artery in PS supports SASDS theory (16). More evidence Tilston’s sketch of the dissected cadaver by Poland omitted in support of SASDS theory was noted in a 4-year-old girl

© Translational Pediatrics. All rights reserved. Transl Pediatr 2021;10(4):1008-1019 | http://dx.doi.org/10.21037/tp-20-320 1010 Hashim et al. PS: theories of its genesis, evolution, and management with below knee right leg hypoplasia and ipsilateral toe osteogenic differentiation of fetal cartilage and cartilage- brachysyndactyly. Her Doppler evaluation revealed 50% bone interface could contribute to PS phenotype. Also, an reduction in femoral artery blood flow (17). Atasoy et al. increase in hexokinase activity (HK1) with 10p duplication has suggested that in a boy with PS, SASDS could have is known to cause CHI (32). caused the manifestations due to thrombosis of the fetal Association of renal with pectoralis major/minor microvasculature as they detected significant mutations in malformations in PS has been linked to acro-renal polytopic his thrombophilia genes (homozygote A1298C MTHFR, field defect. In the embryonic stage of 6–7th week, pectoralis heterozygote Factor V H1299R, and Factor II G20210A mesenchyme separates into pectoralis major and minor and mutations) (18). simultaneously metanephros appears following regression of Several factors, including mechanical, environmental, mesonephros. It was speculated that an insult at this stage of and embryologic events can cause interruption or reduction embryogenesis can cause both pectoral and renal anomalies in blood flow to the subclavian artery and its branches. (27,33). Circumscribed disruption of lateral embryonic plate Intrinsic factors like thrombi and emboli, or external mesoderm causing PS was suggested in an infant with limb mechanical factors like cervical rib, aberrant muscle, body wall defect (27,34). amniotic bands can cause vascular disruption (14,19,20). Extrinsic events, such as the first rib and cervical rib can Epidemiology force the U-shaped configuration of the subclavian artery into a defective configuration, leaving the artery hypoplastic PS occurs in about 1:30,000 live births (35). Incidence (14,21). Other suggested hypotheses include maternal variations have been reported in the past, ranging from around factors, such as smoking and cocaine abuse (22). Smoking 1 in 17,000 live births in Japan and a comparatively lower in pregnancy has shown a two-fold risk of developing PS incidence of 1 in 52,530 live births in Hungary (20). But no in Hungary and Spain (23). However, a case report of a studies have examined ethnicity as an underlying factor for 17-year-old with significant left pectoral muscle deficiency this variation. Incidentally, PS has been diagnosed in 1 of with no arterial alteration has raised questions against the every 19,000 mammograms done during 1985–1995 (36). SASDS theory for pathogenesis of PS (24). Poland syndrome is more often seen in males than females Genetic or extrinsic factors may interfere with the (3:1) and involves more frequently the right side of the body pectoralis major muscle migration and digital separation, than the left, in a ratio of 1.7:1 (37). In sporadic forms, there both occurring between 6 to 8 weeks of gestation (25,26). is male predominance with the right side more affected than Although, most of the PS cases are sporadic, familial cases the left but in females both sides are equally affected. In have been reported. Familial PS raises the question of an familial forms, both sexes are affected equally, and no right- autosomal dominant mode of inheritance with variable side predominance has been reported (15,36). Bilateral penetrance. These familial cases showed intra-familial PS was reported in a young female with bilateral absence variability (27-29). This clinical variability and bilateral of breasts, right pectoral aplasia and absent right ulna and features seen in some cases of PS could be explained by ulnar side of the hand (38). Since then, 15 cases of bilateral paradominant inheritance (30,31). PS have been reported in the literature (39). Lately, a de novo mutation of chromosome 11q12.3 in monozygotic twins with PS was reported. The twins had Clinical spectrum heterozygous deletion in genes which controlled cellular growth, differentiation and apoptosis, which authors The characteristic features of PS include unilateral postulate to be causative of PS. Phenotype concordance hypoplasia/aplasia of the pectoralis major/minor muscles between the female monozygotic twins shed light on this (Figure 1) with variable degree of ipsilateral upper limb mutational role in the genesis of PS (26). anomalies (1,2). Less often, varying degrees of hypoplasia Duplication in the region between 10p13 and 10p14 of latissimus dorsi, deltoid, serratus anterior, supraspinatus, has been reported recently in an infant with congenital infraspinatus and external oblique muscles have been noted. hyperinsulinism (CHI) and PS phenotype. Authors Breast asymmetry to amastia was also reported in more than hypothesized that the duplication in the region between a third of female subjects with PS (40). Often, the nipple 10p13 and 10p14 involving UCMA (upper zone of growth and areola are hypoplastic, less pigmented and elevated. plate and cartilage matrix associated), which control Incidences of athelia and supernumerary nipples although

and fusion of the aplastic ribs may give an appearance of asymmetrical contralateral pectus carinatum due to sternal rotation to the affected side. Severe rib anomalies can result in respiratory dysfunction (42,44-46). In either gender with apparent PS, anterior axillary fold is poorly formed due to aplasia or hypoplasia of the pectoralis major muscle and the posterior fold formed by latissimus dorsi and teres major muscles is visible from the front. Hand-pectoral deformity in PS involves the ipsilateral hand abnormalities, which can vary from syndactyly or symbrachydactyly (89%), short middle phalanges (45%) to rarely ectrodactyly. Hypoplasia of the middle phalanges with cutaneous webbing need not be restricted to digits that Figure 1 Axial CT image shows the normal left pectoralis major are involved in syndactyly and are more often reported in muscle (arrow). The right pectoralis major muscle is not seen on middle phalanges of ulnar side of the hand than radial (47). the opposite side of the chest. Varying degrees of hypoplasia of the upper extremity involving the wrist and hand (89%), forearm (37%), arm (7%) and rarely phocomelia-like deficiency has been reported (27,48). Distortions in digital dermatoglyphics in two cases of PS were reported and since then several authors have attempted to link PS and dermatoglyphics (49-51). Freire-Maia et al. observed zygodactylous triradii associated with a loop, distally placed axial triradii and simian lines in the affected hands of two cases of PS (52). Atasu also reported similar findings in his four cases of PS (53). Characteristic chest and limb defects of PS with abnormal dermatoglyphics were reported in a 10-year-old boy (54). Involvement of lower extremity is rare in PS (17). Unilateral gluteal and lower limb hypoplasia with toe symbrachydactyly was reported with possible disruption of external iliac artery supply (55,56). A Japanese woman with Figure 2 Axial CT image shows the normal left rib (long arrow). PS who had absent right pectoralis major, hypoplastic rib The corresponding right rib is short compared to the left (short cage, underdeveloped breast, short sternum, and scoliosis arrow). also had hypoplasia of the right ilium and gluteus minimus and atrophied right kidney. Contrast CT scan showed disruption of the right internal iliac artery (57). rare, have also been reported (41). Lung herniation (9%) is rare in PS. In some patients with Chest deformities observed in PS includes a keeled chest rib defects, lung herniation occurs only during episodes of (9.7%), followed by hollowed chest (0.8%) (42). Hypoplasia respiratory infection but rarely can occur during normal of the ribs and cartilages leaves a sunken chest wall on the breathing/crying in newborn infants with PS (4,58) (Figures 3,4) affected side. Rib defects are reported in 18% in right- (Video 1). Chest radiograph may reveal hyperlucent lung sided compared to 40% in left-sided PS (43) (Figure 2). fields on the affected side with heart displaced towards Hypoplasia or aplasia occurs more often in second to fourth the unaffected side (4). Isolated dextrocardia was reported or third to fifth ribs and cartilages, but the second rib is in PS with a frequency of 1 in 30,000 live births (59). A less frequently affected (40). Bifid (forked) rib is rare (2%) strong association of dextrocardia with partial agenesis of 2 and scoliosis has been reported in 1.7% of cases with PS. or more ribs was observed and none had congenital heart The chest deformities progress rapidly during growth spurt disease (43). Eventration of diaphragm with PS is a rare

deficiency. Less often café-au-lait spots, cutaneous diffuse neurofibroma, congenital melanocytic nevus and congenital hemangiomas have been reported (63). Increasing number of malignancies has been reported with PS, which includes leukemia, lymphoma, leiomyosarcoma, lung carcinoma, gastric carcinoma, and head and neck tumors. Huang et al. reported 2 cases of invasive ductal carcinoma of the ipsilateral breast in PS. A review of 21 cases of PS with breast cancer in the age range of 33 to 74 years showed pectoral involvement in all (64). The association of congenital anomalies or syndromes with malignancies is well known. This could be attributed Figure 3 Infant with Poland’s syndrome showing the lung to constitutional mutation of both proto-oncogenes herniation on expiration. (Reproduced from Lung herniation: and tumor-suppressor genes, which are known to cause an uncommon presentation of Poland’s syndrome in a neonate congenital anomalies and neoplasms and many of the gene at birth. Chandran S, et al. BMJ Case Rep. 2013 Aug 6;2013, with products play a critical role in signaling pathways, which permission from BMJ Publishing Group Ltd.). control cellular proliferation (65). Other rare congenital anomalies found to be associated with PS incorporate craniofacial dysplasia, microcephaly, Dandy-Walker malformation, and congenital cyanotic heart disease, partial anomalous pulmonary venous return (66). A spectrum of urogenital anomalies has been described with PS varying from hypospadias, duplication of collecting system to agenesis of the kidney (33). A case of coloboma of the optic disc, “Morning glory syndrome” was reported in a 12-year-old with classical PS (67). CHI has been described with PS phenotype in a newborn infant with duplication of the short arm of chromosome 10 (25,32). About 15% of patients with Moebius syndrome have features of PS (68). Moebius-Poland syndrome is estimated Figure 4 Infant showing hypoplasia of the left pectoral muscles to have a prevalence rate of 1 in 500,000 live births. They and areola. On expiration intercostal recession is noted. have VI and VII cranial nerve palsies, upper and lower limb (Reproduced from Lung herniation: an uncommon presentation deformities, and pectoral muscle dysplasia (69). Sprengel’s of Poland’s syndrome in a neonate at birth. Chandran S, et al. BMJ deformity (SD) has been shown to have an association Case Rep. 2013 Aug 6;2013, with permission from BMJ Publishing with PS. It is a rare congenital disorder of pectoral girdle Group Ltd.). with elevation of scapula too high on one side of the body resulting in cosmetic and functional disability. Reported incidence of SD in PS is 15%. Hypoplasia or absence of association, which makes it an entity worth being aware serratus anterior muscle, often affected in PS, results in of when investigating a suspected case of PS especially in varying degrees of elevation and medial winging of the infants with respiratory compromise. The association of scapula (42). Klippel-Feil syndrome characterized by the eventration of diaphragm in PS could support SASDS, triad of a short neck, low posterior hairline, and limitation as the diaphragm is supplied in the embryonic phase of neck movement is a rare congenital anomaly found by branches of the internal thoracic artery, a branch of in association with PS (70). It is caused by the fusion of subclavian artery (60). Hepatic exstrophy and wandering cervical vertebrae. A common etiological theory, viz. the spleen have also been reported in PS (61,62). SASDS theory, has been postulated for Moebius, Klippel- Dermatologic manifestations in PS include pectoral Feil and PS (15,71). and axillary alopecia, anhidrosis and subcutaneous fat It is important to mention that severity of manifestations

© Translational Pediatrics. All rights reserved. Transl Pediatr 2021;10(4):1008-1019 | http://dx.doi.org/10.21037/tp-20-320 Translational Pediatrics, Vol 10, No 4 April 2021 1013 in PS can vary significantly, as some patients present with very of US evaluation for other known associated defects in PS mild forms of chest wall hypoplasia that can be hard to identify should be made, facilitating explicit counseling of parents especially at birth and usually are diagnosed later on in life. regarding fetal outcome. In high-risk families, fetal scan can Cases with mild form of hand anomalies have been diagnosed pick up florid PS as early as the 12th to 13th gestational week near puberty when the limb asymmetry becomes more apparent. even though CHILD syndrome (Congenital hemi-dysplasia with icthyosiform erythroderma and limb defects) can mimic PS especially in the absence of heart defects (76). Classification of anomalies in PS A clinical suspicion of PS arises on detection of chest As PS has widely variable expression and associated defects ± ipsilateral limb defect in a newborn infant or anomalies (Table 1), more than a few classifications of the child. Many cases of PS have been diagnosed at various syndrome were introduced by several authors over the ages, and these may even present to the medical care for years. The main objective of these classifications is to help complaints not related to the syndrome itself. We can surgeons decide about the need of surgical intervention and attribute this diverse age of diagnosis time to the wide the extent of reconstructive surgeries. Seyfer et al. described spectrum of variation in severity of presentations, especially two major forms of PS, a simple form and complex form, in those patients having simple PS with normal hands. and this classification was according to the chest wall defect Absence of anterior axillary fold is recognized in either sex and did not take into consideration the hand anomalies. with apparent PS. Female deformity can vary from breast In the simple form, sterno-costal head of pectoralis major hypoplasia to amastia. Associated ipsilateral thoracic and muscle is absent, and the ipsilateral axillary fold is lacking. limb defects upstage the diagnosis to a severe form of PS. If measured these patients have smaller hemithorax and Mild forms like isolated syndactyly warrants a thorough ipsilateral upper limb. The breast and nipple-areola examination as 10% of these cases will have PS. Abnormal complex are smaller in the affected side. In contrast to dermatoglyphic patterns have been described and may the simple form, the complex form has a notably smaller supplement to make a diagnosis of PS (53). hemithorax and ipsilateral limb hypoplasia sometimes with Imaging modalities are crucial for diagnosis and it brachysyndactyly. In complex form, patients usually have an has an essential role in detecting the specific location axillary web, rudimentary or absent breast and nipple-areola and characteristics of the chest wall deformity. The complex and shorter sternum and clavicle in the affected chest X-ray usually shows lung field hyperlucency in the side (72). More recently, TBN (thorax, breast, nipple-areola affected side, which according to the literature looks like complex) classification was proposed, aiming to include all “a post radical mastectomy picture”. Both the CT and possible phenotypes of PS (73). the MRI are used to enable accurate diagnosis, to show A classification for limb abnormalities in PS has existed the extent of lesions in the musculo-skeletal component, since 1984. Upper extremity anomalies with pectoral agenesis and to help in the surgeon’s decision regarding the best were classified into four types: presence of all digits and modalities for reconstruction. Some authors endorse the mitten hand in type 1, to radial ray defects with absent thumb 3D CT as it demonstrates the extent of the deformity and in type 4 (74). This was further modified to include all type tissue hypoplasia in the most accurate way, which helps of hand anomalies and was classified to seven types; from with planning for transposition of muscular flaps and normal hand (type 1) to phocomelia (type 7) and also it has a reconstructive techniques (77). Preoperative angiography is grading system with increasing severity of hand defects (35). essential to assess the local vascular integrity before planned microvascular tissue transfer (78). PS was first accidentally noted when coexisting pectoral hypoplasia was detected Diagnosis and evaluation of Poland syndrome in mammogram (36). It is also important to assess the Most cases of moderate to severe PS are diagnosed at birth pulmonary function, facilitating surgical decision on the when presented with visible chest or limb defects. Antenatal need for intervention in cases of paradoxical movement of diagnosis using fetal ultrasound scan (US) can detect limb or the chest wall and restrictive lung disease (79). thoracic defects. Doppler assessment of ipsilateral subclavian artery flow is recommended when unilateral skeletal defects Surgical intervention and reconstruction are detected in fetal US. Three-dimensional US can aid in characterization of the limb defect (75). Further attempts Most of the defects seen in PS are of the simple type with

Table 1 Spectrum of anomalies seen in Poland’s syndrome System Anomalies

Musculo-skeletal Absence/hypoplasia of muscles—pectoralis major/minor, deltoid, serratus anterior, supraspinatus, infraspinatus, latissimus dorsi, external oblique and teres major

Hypoplastic hemithorax, Keeled chest/Hollowed chest

Rib aplasia, hypoplasia, bifid ribs(rare)

Winging of scapula (Sprengel’s deformity)

Scoliosis

Hand anomalies—syndactyly, symbrachydactyly, short middle phalanx, ectrodactyly

Hypoplasia of upper arm and forearm/phocomelia

Hypoplasia of the ilium

Unilateral gluteal hypoplasia, lower limb hypoplasia, toe symbrachydactyly (rare)

Breast nipple\areola Mammary hypoplasia/amastia

Nipple-aerolar hypoplasia/hypopigmentation

Supernumerary nipple

Cardiac Dextrocardia

Partial anomalous pulmonary venous return

Respiratory Lung herniation

Eventration of diaphragm

Hematology Coagulation dysfunction

Oncology Leukemia

Non-Hodgkin’s lymphoma

Cervical cancer

Leiomyosarcoma

Lung cancer

Carcinoma of the hypoplastic breast

Gastric carcinoma

Head and neck tumors

CNS head and neck Microcephaly

Craniofacial dysplasia

Dandy-Walker syndrome

Congenital facial nerve palsy (Poland-moebius syndrome)

Renal Unilateral renal agenesis

Duplex ureter

Hypospadias

Abdominal Hepatic exstrophy

Wandering spleen

Table 1 (continued)

Table 1 (continued) System Anomalies

Dermatological Anhidrosis

Ipsilateral alopecia of the pectoral and axillary areas

Café au lait spots

Cutaneous hemangioma

Cutaneous neurofibroma

Congenital melanocytic nevus

Dermatoglyphic abnormalities

Eye Coloboma of the optic disc (morning glory syndrome)

Endocrine Congenital hyperinsulinism

Other syndromes Klippel-Feil syndrome CNS, central nervous system.

mild functional disabilities. Cosmesis remains the most muscle flap transposition (20,72). common indication for repair. Unless there is significant Stem cell therapy has shown some promise in correction respiratory compromise, chest deformities may not need of chest defects and breast augmentation. A 23-year-old any intervention in early life. The vital capacity of the lung female with PS had a successful reconstruction of breast can be as low as 48% depending on the severity of the disease by increasing the density of adipose derived stem cells and may increase up to 68% after surgical correction (80). following two local injections of autologous fat cells (81). We reported a case of PS with significant lung herniation in Lately, a 28-year-old-male with severely affected right neonatal life through the left sided rib defect, which regressed chest due to PS had restoration of pectoral area with spontaneously and remained stable without any intervention injections of adipose-derived mesenchymal stem cells and when last reviewed at 6 years of age (4) (Video 1). fat transfer (82). The proposed mechanisms involved in Generally, surgical intervention may be required for the the role of stem cell transfer include adipose derived stem following indications in PS (3): cells contributing to neoangiogenesis in the acute phase by (I) Unilateral depression of the chest wall with possible functioning as endothelial progenitor cells or as angiogenic- progression with age. factor-releasing cells. The injected fat cells trigger stem (II) Inadequate protection of the lung and heart. cell differentiation within the affected area. So, stem cell (III) Paradoxical movement of the chest wall. therapy could contribute to vascular and muscle growth (IV) Hypoplasia or aplasia of the breast in females. (83,84). (V) Improvement of aesthetic appeal of the chest Reconstructive surgery for limb/hand anomalies aim to contour due to lack of pectoralis major muscle and provide a functional hand in PS and it depends greatly on anterior axillary fold in males. the nature of the deformity. Corrective surgery should be Reconstructive procedures may be required for both planned at an optimal time for symbrachydactyly before chest deformity and limb defects in adolescence. Unilateral flexion contractures and angular deformity sets in. Rarely, depression of the chest wall with severe aplasia of the ribs corrective osteotomies are required for misaligned joints of needs correction in two stages; rib defect repair followed the upper extremity to give a functional hand (85,86). by muscle flap transposition. The most used techniques In summary, the reconstructive surgeries in the chest are the latissimus dorsi flap, or the rectus abdominis flap wall are mostly for cosmetic purposes and any functional if the latissimus dorsi is absent as a part of the syndrome. disability in PS is usually caused by the syndactyly of the The surgical reconstruction should be tailored according hand. Most patients with PS lead a normal life and hardly to each patient’s condition and satisfaction with the results. have any functional limitations. Surgical intervention is In female patients, mammoplasty may be carried out with usually delayed to adolescence, as the correction is mostly

© Translational Pediatrics. All rights reserved. Transl Pediatr 2021;10(4):1008-1019 | http://dx.doi.org/10.21037/tp-20-320 1016 Hashim et al. PS: theories of its genesis, evolution, and management cosmetic, especially in females, unless the patient present studies. Further, establishing an effectual information with severe symptoms that require early intervention. network will promote research and clinical collaboration, Consensus is that delaying the intervention is better as the in turn enhancing the quality of life of patients with varied patient will have an opportunity to make decision regarding forms of PS. the correction, and also to avoid the need for surgical revision with growth (72). Acknowledgments

We thank Prof. Divakaran Liginlal, Carnegie Mellon Genetic counseling University, Pittsburgh, Pennsylvania, USA and Dr. Krishna Presentation of PS in infancy and early childhood is Revanna Gopagondanahalli, Staff Physician, KK Women’s and minimal due to the subtle nature of the pectoral and limb Children’s Hospital, Singapore for editing the manuscript. hypoplasia. The actual incidence in the population could Funding: None. be still underestimated (13). New modalities of imaging like CT/MRI and mammogram are picking up more cases Footnote of minor pectoral and limb defects when investigated for other reasons. A detailed examination of the proband’s first- Reporting Checklist: The authors have completed the degree relatives focusing on minor hand and/or pectoral Narrative Review reporting checklist. Available at http:// defects and dermatoglyphics may unmask a hidden PS dx.doi.org/10.21037/tp-20-320 phenotype (52,53). If positive evidence of PS is found, one may envision a risk of 50% in the offspring (68). The few Conflicts of Interest: All authors have completed the ICMJE familial cases described in the literature had significant uniform disclosure form (available at http://dx.doi. intrafamilial phenotypic heterogeneity, but this indicates org/10.21037/tp-20-320). The authors have no conflicts of some degree of genetic influence (26,28,87). Current interest to declare. evidence is insufficient to provide a good genetic etiology for PS and this supports David’s conclusion that “Poland’s Ethical Statement: The authors are accountable for all anomaly can be regarded as a sporadic condition with an aspects of the work in ensuring that questions related extremely low recurrence risk” (88). to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Written informed consent was obtained from the parents of the child for Conclusions publication of the images. Published figures and video are Historical aspects leave a heated debate on the eponymous reproduced with permission from publisher. origin of PS as several authors have described these paired defects prior to Alfred Poland. This review highlights the Open Access Statement: This is an Open Access article various theories related to the genesis of PS. Partial or full distributed in accordance with the Creative Commons absence of the pectoralis major muscle is mandatory to Attribution-NonCommercial-NoDerivs 4.0 International make the diagnosis. PS has very versatile presentations and License (CC BY-NC-ND 4.0), which permits the non- many systemic associations. Since it was first diagnosed commercial replication and distribution of the article with almost two centuries ago, more associations have been the strict proviso that no changes or edits are made and the added, and different and unusual presentations included. An original work is properly cited (including links to both the extensive spectrum of anomalies described in PS till date formal publication through the relevant DOI and the license). is included in this review. One may conclude that surgical See: https://creativecommons.org/licenses/by-nc-nd/4.0/. intervention is generally done in adolescence mostly for cosmesis but may rarely be needed to improve restrictive References lung diseases in severe chest wall defects. We recommend establishing a PS data registry with 1. Poland A. Deficiency of the pectoral muscles. Guys Hosp systematically collected phenotypic data of affected patients. Rep 1841;6:191-3. The registry will serve to improve knowledge of this rare 2. Clarkson P. Poland’s syndactyly. Guys Hosp Rep musculo-skeletal disorder and facilitate epidemiological 1962;111:335-6.

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Cite this article as: Hashim EAA, Quek BH, Chandran S. A narrative review of Poland’s syndrome: theories of its genesis, evolution and its diagnosis and treatment. Transl Pediatr 2021;10(4):1008-1019. doi: 10.21037/tp-20-320